KR19980032428A - Substituted diamino-1,3,5-triazine derivatives - Google Patents

Abstract

The present invention relates to compounds of the general formula (I), pharmaceutically acceptable acid addition salts and stereochemically isomeric forms thereof for the manufacture of a medicament for the treatment of a patient infected with HIV (human immunodeficiency virus):

In the above formula, R ¹ and R ² are each independently hydrogen; Hydroxy; Amino; Optionally substituted C _1-6 alkyl; C _1-6 alkyloxy; C _1-6 alkylcarbonyl; C _1-6 alkyloxycarbonyl; Ar ¹ ; Mono- or di (Ci_ ₆ alkyl) amino; Mono- or di (Ci_ ₆ alkyl) -aminocarbonyl; Dihydro-2 (3H) -furanone; Or R ¹ and R ² can together form pyrrolidinyl, piperidinyl, morpholinyl, azido or mono- or di (C _1-6 alkyl) amino-C _1-4 alkylidene; R ³ is hydrogen, Ar ¹ , C _1-6 alkylcarbonyl, C _1-6 alkyl, C _1-6 alkyloxycarbonyl, C _1-6 alkyl substituted with C _1-6 alkyloxycarbonyl; R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently hydrogen, halo, C _1-6 alkyl, C _1-6 alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl Or trihalomethyloxy; L is optionally substituted C _1-10 alkyl; C _3-10 alkenyl; C _3-10 alkynyl; C _3-7 cycloalkyl; Ar ¹ is optionally substituted phenyl.

Description

Substituted diamino-1,3,5-triazine derivatives

The present invention relates to novel compounds of formula (I) having HIV replication inhibition properties. The present invention also relates to methods of making such novel compounds, pharmaceutical compositions comprising the novel compounds and their use as drugs.

Structurally related compounds related to the novel compounds of the present invention are disclosed in the prior art. DE-2,121,694, published November 25, 1971, discloses a variety of s-triazines that are useful as anti-inflammatory, sedative, antiviral, antispasmodic, hypoglycemic, diuretic, vasodilator agents and to reduce corticosteroid secretion. have. February 22, 1973, DE-2,226,474 discloses a diamino-1,3,5-triazine derivative having hormonal secretion-increasing activity and anti-inflammatory effect. Substituted triazines with diuretic effect are described in Guioca, Ann. Pharm. Fr., 31: 283-292 (1973). Several 2,4-diamino-triazines are described in Kelarev VI et al., Khim. Geterotsikl. Soedin., 1392-1397 (1987) and Kelarev VI et al., Khim. Geterotsikl. Soedin., 1395-1399 (1992). The preparation of 2-amino-4-benzyl-6-o- toluidino- s-triazine is disclosed in Yuki Y. et al., Kobunshi Kagaku, 26: 141-147 (1969). The use of aralkylguanamines, in particular 2-amino-4-anilino-6-benzyl-s-triazine, for the preparation of resins is disclosed in US Pat. No. 2,817,614, filed December 24, 1957.

Incidentally, it was found that the compounds of formula (I) effectively inhibit the replication of human immunodeficiency virus (HIV) and eventually found useful in the treatment of HIV infected individuals.

The present invention relates to the use of the compounds of formula (I), pharmaceutically acceptable acid addition salts and stereochemically isomeric forms thereof for the manufacture of a medicament for the treatment of a patient infected with HIV (human immunodeficiency virus). :

In the above formula,

R ¹ and R ² are each independently hydrogen; Hydroxy; Amino; C _1-6 alkyl; C _1-6 alkyloxy; C _1-6 alkylcarbonyl; C _1-6 alkyloxycarbonyl; Ar ¹ ; Mono- or di (Ci_ ₆ alkyl) amino; Mono- or di (Ci_ ₆ alkyl) aminocarbonyl; Dihydro-2 ( 3H ) -furanone; Each independently amino, imino, aminocarbonyl, aminocarbonylamino, hydroxy, hydroxyC _1-6 alkyloxy, carboxyl, mono- or di (C _1-6 alkyl) amino, C _1-6 alkyl Selected from substituted C _1-6 alkyl as one or two substituents selected from oxycarbonyl and thienyl; or

R ¹ and R ² can together form pyrrolidinyl, piperidinyl, morpholinyl, azido or mono- or di (C _1-6 alkyl) aminoC _1-4 alkylidene;

R ³ is hydrogen, Ar ¹ , C _1-6 alkylcarbonyl, C _1-6 alkyl, C _1-6 alkyloxycarbonyl, C _1-6 alkyl substituted with C _1-6 alkyloxycarbonyl;

R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently hydrogen, hydroxy, halo, C _1-6 alkyl, C _1-6 alkyloxy, cyano, aminocarbonyl, nitro, amino, tri Selected from halomethyl or trihalomethyloxy;

L is C _1-10 alkyl; C _3-10 alkenyl; C _3-10 alkynyl; C _3-7 cycloalkyl; or

L is independently C _1-10 alkyl substituted with one or two substituents selected from C _3-7 cycloalkyl; Indolyl or each independently halo, C _1-6 alkyl, C _1-6 alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy, C _1-6 alkylcarbonyl Indolyl substituted as one, two, three or four substituents selected from; Phenyl or each independently halo, hydroxy, C _1-6 alkyl, C _1-6 alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy, C _1-6 alkyl Phenyl substituted as one, two, three, four or five substituents selected from carbonyl;

Ar ¹ is phenyl or phenyl each independently substituted with one, two or three substituents selected from halo, C _1-6 alkyl, C _1-6 alkyloxy, cyano, nitro or trifluoromethyl.

The present invention also provides novel compounds of the following general formula (I '), pharmacologically acceptable acid addition salts, wherein the substituents are defined in general formula (I), provided that the following compounds (a) to (o) are not included: And stereochemically isomeric forms.

Co.No. Alk R ¹ / R ² R ³ R ⁴ R ⁵ R ⁶ R ⁷ R ⁸ abcdefghijklmno 1- (4- (2-methylpropyl) phenyl) ethyl1- (4- (2-methylpropyl) phenyl) ethyl1- (4- (2-methylpropyl) phenyl) ethyl1- (4- (2- Methylpropyl) phenyl) ethyl1- (4- (2-methylpropyl) phenyl) ethyl4- (2-methylpropyl) phenylmethyl1- (4- (2-methylpropyl) phenyl) ethyl4- (2-methyl Propyl) phenylmethyl3,4-dimethoxyphenylmethyl2,3-dimethoxyphenylmethyl3,4-diethoxyphenylmethyl2- (3,5- (1,1-dimethylethyl) -4-hydroxy-phenyl ) Ethyl2- (3,5- (1,1-dimethylethyl) -4-hydroxy-phenyl) ethylphenylmethylphenylmethyl H / HH / HH / HH / HH / HH / HH / HH / HH / HH / HH / HH / HH / HH / HH / H HHC ₆ H ₅ HHHHHHHHHHHH CH ₃ HHNO ₂ HHHHHHHHHCH ₃ H HHHHHCF ₃ HHHHHHt-BuHH HNO ₂ HCH ₃ NH ₂ HClHHHHHOHHH HHHHHHHHHHHHt-BuHH HHHHHHHHHHHHHHH

Such conditions include compounds (a) to (f) disclosed in DE-2,121,694 and DE-2,226,474; Compound (g) disclosed in DE-2,226,474; Guioca, Ann. Fr., compounds (h) to (k) disclosed in 31: 283-292 (1973); Kelarev VI et al., Khim. Geterotsikl. Soedin., Compound (l) disclosed in 1392-1397 (1987); Kelarev VI et al., Khim. Geterotsikl. Soedin., Compound (m) disclosed in 1395-1399 (1992); Compound (n) disclosed in Yuke Y. et al., Kobunshi Kagaku , 26: 141-147 (1969); And compound (o) disclosed in US Pat. No. 2,817,614.

As used in the previous definitions and hereinafter halo means fluoro, chloro, bromo and urethra; C _1-2 alkyl includes methyl and ethyl; C _1-3 alkyl means straight and branched chain saturated hydrocarbon radicals having 1 to 3 carbon atoms such as, for example, methyl, ethyl, propyl and the like; C _1-4 alkyl includes its higher homologs containing four carbon atoms such as, for example, butyl, in addition to the straight and branched chain saturated hydrocarbon radicals defined in C _1-3 alkyl; C _1-6 alkyl includes straight and branched chain saturated hydrocarbon radicals as defined in C _1-4 alkyl as well as higher homologues thereof containing 5 or 6 carbon atoms such as, for example, pentyl or hexyl; C _3-6 alkyl means straight and branched chain saturated hydrocarbon radicals having 3 to 6 carbon atoms such as, for example, propyl, butyl, pentyl, hexyl and the like; C _2-6 alkyl includes ethyl in addition to the straight and branched chain saturated hydrocarbon radicals defined in C _3-6 alkyl; C _1-10 alkyl includes straight and branched chain saturated hydrocarbon radicals as defined in C _1-6 alkyl as well as higher homologues thereof containing for example 7 to 10 carbon atoms such as heptyl, octyl, nonyl or decyl; C _1-4 alkylidene means divalent straight and branched chain hydrocarbons having 1 to 4 carbon atoms such as, for example, methylene, ethylidene, propylidene, butylidene and the like; C _3-7 cycloalkyl is collectively cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; C _3-10 alkenyl is for example 2-propenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, 3-hexenyl, 3-heptenyl, 2- Refers to straight and branched chain hydrocarbon radicals containing one double bond having 3 to 10 carbon atoms such as octenyl, 2-nonenyl, 2-decenyl and the like; The carbon atom bonded to the triazine ring is thus preferably an aliphatic carbon atom; C _3-10 alkynyl is for example 2-propynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 3-methyl-2-butynyl, 3-hexynyl, 3-heptinyl, 2- By straight and branched chain hydrocarbon radicals containing one triple bond and having from 3 to 10 carbon atoms, such as octinyl, 2-noninyl, 2-decynyl, etc., wherein the carbon atoms bonded to the triazine ring are preferably aliphatic carbons. An atom; C _1-6 alkanediyl is for example methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl and side chain isomers thereof. As used herein, divalent straight and branched chain saturated hydrocarbon radicals having 1 to 6 carbon atoms are meant.

Pharmaceutically acceptable acid addition salts mentioned above include non-toxic acid addition salt forms with therapeutic activity in which compounds of formula (I) or (I ') may be formed. Basic compounds of formula (I) or (I ') can be converted to pharmaceutically acceptable acid addition salts by treating the base form with a suitable acid. Examples of suitable acids include hydrofluoric acid, such as hydrochloric acid or hydrobromic acid; Sulfuric acid; nitric acid; Inorganic acids such as phosphoric acid and the like; Or acetic acid, propanoic acid, hydroxyacetic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid (ie butanedioic acid), maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p Organic acids such as toluenesulfonic acid, cyclamic acid, salicylic acid, p-amino-salicylic acid, pamonic acid and the like.

Addition salts also include hydrates and solvent addition forms in which compounds of formula (I) or (I ') may be formed. Examples of such forms are hydrates, alcoholates and the like.

As used previously, stereochemically isomeric forms of compounds of formula (I) or (I ') consist of identical atoms bonded by bonds of the same sequence, but are not compatible, and are of formula (I) or (I It means all possible compounds with different three-dimensional structures that compounds of ') can possess. Unless otherwise stated or indicated, the chemical name of a compound includes mixtures of possible stereochemically isomeric forms that the compound may have. The mixture may contain both diastereomers and / or enantiomers of the basic molecular structure of the compound. All stereochemically isomeric forms of the compounds of formula (I) or (I ') are intended to be included in the scope of the invention as pure forms or as mixtures with one another.

Some of the compounds of formula (I) or (I ') may also exist in tautomeric forms. Such forms are not explicitly set forth in the foregoing, but are intended to be included within the scope of the present invention.

The compound of general formula (I) or (I ′) is always hereafter meant to include pharmaceutically acceptable acid addition salts and all stereoisomeric forms.

Particular groups of compounds are compounds of formula (I-P) and include compounds of formula (I) or (I ') having the following substituent definitions:

In the above formula

R ¹ and R ² are each independently selected from hydrogen, C _1-6 alkyl, Ar ¹ or mono- or di (C _1-6 alkyl) aminocarbonyl; or

R ¹ and R ² can together form pyrrolidinyl, piperidinyl or morpholinyl;

R ³ is hydrogen, C _1-6 alkyl or Ar ¹ ;

Ar ¹ is phenyl or phenyl each independently substituted with 1, 2 or 3 substituents selected from halo, C _1-6 alkyl, C _1-6 alkyloxy, cyano, nitro or trifluoromethyl;

L is a radical of the formula

Wherein Alk is C _1-6 alkanediyl;

R ^a , R ^b , R ^c , R ^d , R ^e , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently hydrogen, halo, C _1-6 alkyl, C _1-6 alkyloxy, Cyano, aminocarbonyl, nitro, amino, trihalomethyl or trihalomethyloxy; or

R ^a and R ^b together can form a divalent radical of the formula

-C = H = CH-NR ^9- (a-1),

-NR ⁹ -CH = CH- (a-2),

Wherein R ⁹ is hydrogen or C _1-4 alkyl.

Another specific group of compounds are those of the general formula (I-P) excluding compounds (a) to (o), which compounds are represented by the general formula (I'-P).

Compounds of interest are compounds of formula (I ') wherein NR ¹ R ² is not amino.

Other compounds of interest include L is C _1-10 alkyl; C _3-10 alkenyl; C _3-10 alkynyl: C _3-7 cycloalkyl; Or C _1-10 alkyl wherein L is substituted with one or two substituents independently selected from C _3-7 cycloalkyl; Indolyl or each independently halo, C _1-6 alkyl, C _1-6 alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy, C _1-6 alkylcarbonyl Indolyl substituted as one, two, three or four substituents selected from among them; Each independently selected from halo, C _1-3 alkyl, C _3-6 alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy, C _1-6 alkylcarbonyl Is a phenyl substituted as dog, two, three, four or five substituents.

Another compound of interest is a compound of formula (I) to which one of the following limitations applies:

i) R ⁴ is hydroxy, halo, C _2-6 alkyl, C _1-6 alkyloxy, cyano, aminocarbonyl, amino, trihalomethyl or trihalomethyloxy; or

ii) R ⁵ is hydroxy, halo, C _1-3 alkyl, C _1-6 alkyloxy, cyano, aminocarbonyl, nitro, amino, or trihalomethyloxy; or

iii) R ⁶ is C _2-6 alkyl, C _1-6 alkyloxy, cyano, aminocarbonyl, nitro, trihalomethyl or trihalomethyloxy; or

iv) R ⁷ is hydroxy, halo, C _1-3 alkyl, C _1-6 alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl or trihalomethyloxy; or

v) R ⁸ is hydroxy, halo, C _1-6 alkyl, C _1-6 alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl or trihalomethyloxy.

Specific compounds include C _3-10 alkenyl or C _1-2 alkyl wherein L is independently substituted with one or two substituents selected from C _3-7 cycloalkyl; Indolyl or each independently halo, C _1-6 alkyl, C _1-6 alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy, C _1-6 alkylcarbonyl Indolyl substituted as one, two, three or four substituents selected from among them; Phenyl or each independently halo, hydroxy, C _1-6 alkyl, C _1-6 alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy, C _1-6 alkyl Phenyl substituted as one, two, three, four or five substituents selected from carbonyl; More specifically, C _5-8 alkenyl or C _1-2 alkyl wherein L is independently substituted with one or two substituents selected from cyclopropyl; Indolyl substituted with indolyl or halo; Phenyl or each independently one, two, three selected from halo, hydroxy, C _1-6 alkyl, C _1-6 alkyloxy, trihalomethyl, trihalomethyloxy, C _1-6 alkylcarbonyl Is a compound of formula (I) or (I ') which is phenyl substituted as a dog, four or five substituent.

And specific compounds are those in which R ⁴ , R ⁷ and R ⁸ are hydrogen and R ⁵ and R ⁶ are each independently hydrogen, cyano, halo or aminocarbonyl; More specifically, it is a compound of general formula (I) or (I ') whose R <^4> , R <^5> , R <^7> and R <^8> are hydrogen and R <^6> is cyano.

Other specific compounds include those wherein R ¹ and R ² are each independently hydrogen; Hydroxy; Amino; C _1-6 alkyl; C _1-6 alkoxyoxy; C _1-6 alkylcarbonyl; C _1-6 alkyloxycarbonyl; Ar ¹ ; Mono- or di (Ci_ ₆ alkyl) aminocarbonyl; Dihydro-2 (3H) -furanone; Each independently amino, imino, aminocarbonyl, aminocarbonylamino, hydroxy, hydroxyC _1-6 alkyloxy, carboxyl, mono- or di (C _1-6 alkyl) amino, C _1-6 alkyl Selected from substituted C _1-6 alkyl as one or two substituents selected from oxycarbonyl and thienyl; Or R ¹ and R ² together form azido or mono- or di (C _1-6 alkyl) aminoC _1-4 alkylidene; More specifically, R ¹ is hydrogen and R ² is hydrogen; Hydroxy; Amino; C _1-6 alkyl; C _1-6 alkyloxy; C _1-6 alkylcarbonyl; C _1-6 alkyloxycarbonyl; Ar ¹ ; Mono- or di (Ci_ ₆ alkyl) aminocarbonyl; Dihydro-2 (3H) -furanone; Each independently amino, imino, aminocarbonyl, aminocarbonylamino, hydroxy, hydroxyC _1-6 alkyloxy, carboxyl, mono- or di (C _1-6 alkyl) amino, C _1-6 alkyl Or a compound of formula (I) or (I ') which is C _1-6 alkyl substituted as one or two substituents selected from oxycarbonyl or thienyl.

A preferred group of compounds is a compound of formula (I) or (I '), wherein L is 2,6-dichlorophenylmethyl.

Another preferred group of compounds is a compound of formula (I) or (I ') wherein R ³ is hydrogen, R ⁴ , R ⁵ , R ⁷ and R ⁸ are hydrogen and R ⁶ is cyano.

Another preferred compound group is a compound of formula (I) or (I ') wherein R ¹ is hydrogen and R ² is hydrogen or hydroxy.

Compounds of the general formula (I) or (I ') wherein L is 2,6-dichlorophenylmethyl, R ³ is hydrogen, R ⁴ , R ⁵ , R ⁷ and R ⁸ are hydrogen and R ⁶ is cyano desirable.

Most preferred compounds are 4-[[4-amino-6-[(2,6-dichlorophenyl) methyl] -1,3,5-triazin-2-yl] amino] benzonitrile; 4-[[4- (2,6-dichlorophenyl) methyl] -6- (hydroxyamino) -1,3,5-triazin-2-yl] amino] benzonitrile and its pharmaceutically acceptable acid moieties It is salting.

In general, the compounds of formula (I) are described in DE-2,121,694, DE-2,226-474 and Guioca, Ann. Pharm. Fr. , 31: 283-292 (1973).

A compound of formula (Ia), wherein R ¹ and R ² are hydrogen, is a compound of formula (I) wherein the intermediate of formula (II) is prepared in a reaction-inert solvent such as N, N-dimethylformamide. Can be prepared by reacting with the intermediate of III).

A compound of formula (Ib), wherein R ³ is hydrogen, is a compound of formula (I) wherein the intermediate of formula (IV) is prepared in a reaction-inert solvent such as N, N-dimethylformamide It can be prepared by reaction with an intermediate.

L is indolyl or each independently halo, C _1-6 alkyl, C _1-6 alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy, C _1-6 alkyl C _1-10 alkyl substituted as indolyl substituted as one, two, three or four substituents selected from carbonyl, and the substituents are represented by (R ′) n wherein n is from 1 to 4; Compounds of formula (I) represented by formula (Ic) are known in the art, such as refluxing in the presence of a base such as potassium carbonate in a reaction-inert solvent such as water, methanol or mixtures thereof. According to the deprotection techniques described above, P can be prepared by deprotecting the intermediate of formula (VI), for example a suitable protecting group such as toluenesulfonyloxy group and the like.

Compounds of formula (I) wherein R ¹ is hydrogen and the compound is represented by formula (Id) are suitable bases in reaction inert solvents such as 1,4-dioxane and the like, such as sodium hydroxide, triethylamine or In the presence of N, N-diisopropylamine and the like, an intermediate of formula (VII), in which W ¹ is a suitable leaving group such as, for example, halogen, can be prepared by reacting with an amino derivative of formula (VIII).

If R ² contains a hydroxy component, the hydroxy component produces a suitable protecting group P, for example a trialkylsilyl group, and then as a protective form of intermediate (VIII) by removing the protecting group according to methods known in the art. It is convenient to carry out the reaction.

The compound of formula (I) wherein R ¹ and R ³ are hydrogen and R ² and C ₆ (R ⁴ R ⁵ R ⁶ R ⁷ R ⁸ ) are the same and the compound is represented by formula (Ie) reacts Intermediates of formula (IX), in which W ² is a suitable leaving group such as, for example, halogen, in an inert solvent such as 1,4-dioxane can be prepared by reacting with an intermediate of formula (X).

Compounds of general formula (I) in which R ¹ and R ² are not hydrogen and are represented by R ^{1 '} and R ^2' , respectively, and the compound is represented by general formula (If-1), are for example N, N-dimethyl Intermediate of general formula (XI) in a reaction-inert solvent such as formamide or N, N-dimethylacetamide and in the presence of a suitable base such as sodium hydride or potassium carbonate is a suitable leaving such that W ³ is for example halogen It can be prepared by reaction with an intermediate of the general formula (XII).

When intermediate (XII) is limited to W ³ -Ar ¹ (XII-b) and R ³ is hydrogen, the reaction time may be adjusted to form a disubstituted homologue represented by formula (If-2).

Compounds of formula (I) may also be prepared by converting compounds of formula (I) to one another according to group conversion reactions known in the art.

For example, compounds of formula (Ia) may be selected from the anhydrides of formula (XIII) and Arch, wherein R is defined such that -C (= 0) -R is part of the definition of R ¹ or R ² . The reaction can be carried out according to the method described in Pharm. (Waldheim) 1986, 319, 275, thus forming a compound of formula (Ig). In this reaction, the reflux time is important; Longer times lead to lower yields of monosubstituted end products and to increased formation of di- and possibly trisubstituted end products.

*: Only if R ³ is hydrogen

The compounds of formula (I-a) can also be reacted with reagents of formula (XIV) in a reaction-inert solvent such as, for example, N, N-dimethylformamide, in the presence of a base such as sodium hydride.

Some of the intermediates mentioned above may be commercially available or prepared according to methods known in the art, while other intermediates are considered novel.

Intermediates of formula (II) may be prepared by reacting a cyano derivative of formula (XV) with ammonium chloride (XVI) or a functional derivative thereof in the presence of a suitable catalyst such as trimethylaluminum in a reaction inert solvent such as toluene.

Intermediates of formula (III) are generally described in Webb RL et al., J. Heterocyclic Chem. , Diphenyl N-cyanocarbonimidate of formula (XVII), which may be prepared according to 19: 1205-1206 (1982), reacts with an aniline derivative of formula (XVIII), such as N, N- It can be prepared by reaction in dimethylformamide.

The intermediate of formula (VII) is initially a Grignard reagent which is an intermediate of formula (XIX) where W ⁴ is a suitable leaving group such as halogen, e.g. bromine, in the presence of magnesium in a reaction-inert solvent such as diethyl ether. And the Grignard reagent is then reacted with an intermediate of formula (XX) in which W ⁵ is a suitable leaving group such as, for example, halogen, eg chlorine, in a reaction-inert solvent such as benzene to give the formula (XXI) It can be prepared by forming an intermediate. It is convenient to carry out the reaction under an inert atmosphere such as argon. The intermediate (XXI) can be separated from its reaction medium, or further added to the intermediate of general formula (XXII) in a reaction-inert solvent such as 1,4-dioxane and in the presence of a suitable base such as diisopropylethanamine and the like. In-situ reaction may form an intermediate of formula (VII). Intermediates of formula (VII) are considered novel.

Intermediates of formula (XI) may be prepared by reacting the intermediate of formula (XXIII) with the intermediate of formula (XXIV) in a reaction-inert solvent such as N, N-dimethylformamide.

Some of the compounds of formula (I) and intermediates may have one or more sterogenic centers, present in R or S form in their structure.

The compounds of formula (I) prepared by the process described above can be synthesized in the form of mixtures of stereoisomeric forms, in particular racemic mixtures of enantiomers which can be separated from one another according to the splitting methods known in the art. . Racemic compounds of formula (I) can be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. The diastereomeric salt forms are then separated, for example by selective or fractional crystallization and the enantiomers are liberated by alkali. Another way of separating the enantiomer form of the compound of formula (I) involves liquid chromatography using a chiral stationary phase. Pure stereochemically isomeric forms can also be derived from the corresponding pure stereochemically isomeric forms of suitable starting materials, provided that the reaction occurs stereospecifically. Preferably, if a specific stereoisomer is desired, the compound will be synthesized by stereospecific preparation. These methods would be advantageous to use pure starting materials of enantiomers.

Compounds of general formula (I) exhibit antiretroviral properties, particularly against human immunodeficiency virus (HIV), which is the pathogen of human acquired immunodeficiency syndrome (AIDS). The HIV virus selectively infects human T-4 cells and destroys them or alters their normal function, especially the coordination of the immune system. As a result, the number of T-cells in infected patients is constantly decreasing, and these T-cells are moreover behaving abnormally. Thus, the immunological defense system cannot fight infections and neoplasms and HIV-infected patients are usually killed by opportunistic infections such as pneumonia or by cancer. Other symptoms related to HIV include infection of the central nervous system characterized by thrombocytopenia, Kaposi's sarcoma and progressive dehydration leading to symptoms such as dementia and progressive dysarthria, limb dysfunction and confusion. HIV infection has also been linked to peripheral neuropathy, progressive comprehensive lymphadenopathy (PGL) and AIDS-related complexes (ARC).

Compounds of the invention also exhibit activity against HIV-1 strains with acquired resistance to non-nucleoside reverse transcriptase inhibitors known in the art. They also have little or no binding affinity for human α-1 acid glycoproteins.

Due to their antiretroviral properties, specifically their anti-HIV properties, especially their anti-HIV-1-activity, the compounds of general formula (I), their pharmaceutically acceptable salts and stereochemically isomeric forms are infected with HIV It is useful in the treatment of individuals and for the prevention of these individuals. In general, the compounds of the present invention may be useful for the treatment of infected warm-blooded animals as viruses whose survival is mediated or dependent on the enzyme reverse transscriptase. Symptoms that can be prevented or treated as a compound of the present invention, especially those associated with HIV and other pathogenic retroviruses, are caused by AIDS, AIDS-related complexes (ARCs), advanced comprehensive lymphadenopathy (PGL), and other retroviruses. Chronic CNS diseases such as HIV mediated dementia and multiple sclerosis.

Thus the compounds of the present invention can be used as drugs for the above-mentioned symptoms. The use as a drug or method of treatment involves systemically administering to HIV-infected patients an effective amount against HIV and other pathogenic retroviruses, particularly HIV-1 associated symptoms.

Subject compounds may be formulated in a variety of formulations depending on the purpose of administration. The formulations or compositions are considered novel and consequently constitute another embodiment of the present invention. The preparation of the composition also constitutes a further example of the invention. As suitable compositions, all compositions commonly used in systemically administered drugs can be cited. To prepare a pharmaceutical composition of the present invention, the active ingredient is formulated in an effective amount of a particular compound, optionally in admixture with a pharmaceutically acceptable carrier in the form of acid addition salts, which carrier may take a wide variety of forms depending on the form of preparation useful for administration. Can be. These pharmaceutical compositions are particularly useful in single dosage forms suitable for oral, rectal, transdermal or parenteral injection. For example, in preparing the compositions in oral dosage form, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as conventional pharmaceutical media such as suspensions, syrups, elixirs and solutions; Or solid carriers such as starch, sugars, kaolin, glidants, binders, disintegrants and the like in the case of powders, pills, capsules, and tablets. Because of their ease of administration, tablets and capsules represent the most useful oral dosage unit forms, in which case clearly solid pharmaceutical carriers are used. For parenteral compositions, the carrier will typically include other ingredients, such as dissolution aids, but will at least mostly contain sterile water. For example, injectable solutions may be prepared in which the carrier comprises saline, a glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which suitable liquid carriers, suspending agents and the like may be used. Also included are solid form preparations which allow for conversion to the liquid form immediately prior to use. In compositions suitable for transdermal administration, the carrier optionally comprises a penetration enhancer and / or a suitable humectant and is optionally combined in small amounts with a suitable additive of any property that does not exhibit significant adverse effects on the skin.

Particular preference is given to combining the abovementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically divided units as a single dose, each containing an amount of active ingredient calculated to produce the desired therapeutic effect in association with the desired pharmaceutical carrier. Examples of such dosage unit forms include tablets (including wired or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, and their multiples. to be.

An HIV-infected treatment expert can determine the effective daily amount from the test results presented herein. In general, an effective daily amount is expected to be from 0.01 mg / kg to 50 mg / kg body weight, more preferably from 0.1 mg / kg to 10 mg / kg body weight. The desired dosage can be administered in two, three, four or more in duplicates at appropriate intervals throughout the day. The dosage can be formulated, for example, as unit dosage form containing 1 to 1000 mg of active ingredient per unit dosage form, and in particular 5 to 200 mg.

The exact dosage and frequency of administration are well known to those skilled in the art, such as the compound of formula (I) used, the specific condition being treated, the severity of the condition being treated, the age, weight and overall physical condition of the particular patient. And other medications that an individual can take. It is also evident that the daily effective amount can be lowered or increased depending on the response of the treated patient and / or according to the evaluation of the practitioner who prescribes the compound of the invention. The above-mentioned effective daily ranges are therefore only guidelines and are not intended to limit the scope or use of the invention.

In addition, combinations of antiretroviral compounds and compounds of formula (I) may be used as drugs. Accordingly, the present invention also relates to a product containing (a) a compound of formula (I) and (b) another antiretroviral compound as a binding agent for simultaneous, separate or continuous use in anti-HIV treatment. Different drugs can be combined into a single agent, just like pharmaceutically acceptable carriers. Such other antiretroviral compounds are known antiretroviral compounds such as nucleoside reverse transscriptase inhibitors such as zidovudine (3'-azido-3'-deoxythymidine, AZT), didanosine (didenosine). Oxy inosine, ddI), zalcitabine (dideoxycytidine, ddC) or lamivudine (3'-thia-2 ', 3'-dideoxycytidine, 3TC) and the like; Non-nucleoside reverse transscriptase inhibitors such as suramin, pentamidine, thymopentin, castanospermine, dextran (dextran sulfate), foscarnesodium (trisodium phosphono formate), nevirapine (11-cyclo Propyl-5,11-dihydro-4-methyl-6H-dipyrido [3,2-b: 2 ', 3'-e] [1,4] diazepin-6-one), tacrine (tetrahydro Aminoacridine); TIBO (tetrahydro-imidazole [4,5,1-jk] [1,4] -benzodiazepine-2 (1H) -one and thion) -type compounds such as (S) -8-chloro-4, 5,6,7-tetrahydro-5-methyl-6- (3-methyl-2-butenyl) imidazo- [4,51-jk] [1,4] benzodiazepine-2 (1H) -thione; compounds of the α-APA (α-anilino phenyl acetamide) type, for example α-[(2-nitro-phenyl) amino] -2,6-dichlorobenzene-acetamide; TAT-inhibitors such as RO-5-3335 and the like; Protease inhibitors such as indinavir, ritanovir, saquinovir and the like; Or immunomodulators such as levamisol and the like.

The following examples illustrate the scope of the invention and are not intended to limit it.

Experiment

RT means room temperature, DCM means dichloromethane, DMF means N, N-dimethylformamide and ACN means acetonitrile.

A. Preparation of Intermediates

Example A.1

a) A mixture of 4-cyano-aniline (2.48 g) and diphenyl N-cyano-carbonimidate (5.0 g) in DMF (25 mL) was stirred at 110 ° C. for 20 hours under an argon stream. Water was added and the resulting precipitate was filtered to give a brown solid. This fraction was recrystallized in ACN. The precipitate was filtered off and dried to give 1.67 g (30%) of phenyl N'-cyano-N- (4-cyanophenyl) carbamidate (intermediate 1). Phenyl N'-cyano-N- (3-cyanophenyl) carbaimidate (intermediate 2) in a similar manner; Phenyl N'-cyano-N- (4-chlorophenyl) carbaimidate (intermediate 3) and O-phenyl N'-cyano-N, N-dimethylcarbimidate (intermediate 7) were prepared.

b) A mixture of intermediate (7) (0.01746 mol) and 2,6-dichloro-benzene-ethaneimideamide (0.01746 mol) in DMF (30 mL) was stirred at 85 ° C for 24 h. After cooling, the reaction mixture was quenched with H ₂ O and the precipitate was filtered and dried to give 6-[(2,6-dichlorophenyl) methyl] -N2-dimethyl-1,3,5-triazine-2,4- 5.00 g (96.0%) of diamine (intermediate 31) were obtained.

Example A.2

a) A mixture of NH ₄ Cl (2.55 g) in toluene (100 mL) was stirred under an argon stream and cooled in an ice bath. Al (CH ₃ ) ₃ / toluene (23.9 mL; 2.0 M) was added and the resulting mixture was stirred at RT for 1.5 h. 5-chloro-1-[(4-methylphenyl) -sulfonyl] -1H-indole-4-acetonitrile, which may be prepared according to Matsumoto et al., Heterocycles , 24 (11), 3157-3162 (1986). 3.0 g) was added and the reaction mixture was stirred at 80 ° C for 24 h. The reaction mixture was then poured into a slurry of 96 g of silica gel in DCM (200 mL), stirred and filtered, then the filter cake was washed with methanol (400 mL) and evaporated to give 5.35 g of a white solid. The solid is dissolved in DCM, washed with 3N NaOH, dried as potassium carbonate, filtered and the filtrate is evaporated to 5-chloro-1-[(4-methylphenyl) sulfonyl] -1H-indole- 2.80 g (89%, white solid) of 4-ethaneimideamide (intermediate 4) was obtained.

b) A mixture of intermediate (4) (2.61 g) and intermediate (1) (1.89 g) in DMF (25 mL) was stirred for 24 h at 65 ° C. under argon. Water was added slowly and the precipitate was filtered to give 3.55 g of an off white solid. The solid was stirred at reflux in ACN, cooled and filtered to give 2.54 g (66%) of a white solid. 0.30 g of the sample was recrystallized in methanol. The precipitate was filtered off and dried to give 4-[[4-amino-6-[(4-cyanophenyl) amino] -1,3,5-triazin-2-yl] methyl] -5-chloro-1- 0.28 g (62%, white solid) of [(4-methylphenyl) sulfonyl] -1H-indole (intermediate 5) was obtained. A list of intermediates prepared according to the method described in Example A.2a is shown in Table 1.

Example A.3

Udodomethane (1.76 mL) was added to 4-cyanophenyl-thiourea (5.0 g) in acetone (100 mL). The reaction mixture was stirred at rt overnight. The precipitate was filtered off, dried and dissolved in DCM. The organic solution is washed as NH ₃ (aq.) (Excess), dried as potassium carbonate, filtered and the solvent is evaporated to methyl N '-(4-cyanophenyl) -carbamimidothioate (Intermediate 6 4.53 g (84%, white solid) were obtained.

Example A.4

a) a solution of 2- (bromomethyl) -1,3-dichlorobenzene (about 10% of 0.383 mol) in diethyl ether (240 ml) to argon in magnesium (0.383 mol) in diethyl ether (240 ml) Under addition. Once the reaction started, the residual amount of 2- (bromomethyl) -1,3-dichlorobenzene in diethyl ether was added. The solution was stirred at RT for 2.5 h and then quenched by cannula to a solution of benzene (480 mL) and 2,4,6-trichloro-1,3,5-triazine (0.319 mol) while maintaining the temperature below 15 ° C. Added. The reaction mixture was stirred for 1 hour in an ice bath and then for 2 hours at RT. A solution of N, N-diisopropylethylamine (61.0 mL) and 4-amino-benzonitrile (0.351 mol) in 1,4-dioxane (500 mL) was added and the reaction mixture was stirred at RT for 40 h. The solvent was evaporated. Water and ethyl acetate were added. After stirring the solution, the solid was filtered off, washed with ethyl acetate and water, and then 4-[[4-chloro-6-[(2,6-dichlorophenyl) methyl] -1,3,5-triazine- 129.9 g of 2-yl] -amino] benzonitrile (intermediate 27; mp. 243-244 ° C) were obtained. In a similar manner, 4-[[4-chloro-6-[(2,4-dichlorophenyl) methyl] -1,3,5-triazin-2-yl] -amino] benzonitrile (intermediate 28) and 4 -[[4-chloro-6-[(2-chlorophenyl) methyl] -1,3,5-triazin-2-yl] amino] benzonitrile (intermediate 29) was prepared.

b) 2,4-dichloro-6-[(2,6-dichlorophenyl) methyl] -1,3,5-tri according to the method described in Example A.4a but stopped before addition of 4-aminobenzonitrile A azine (intermediate 30) was prepared.

B. Preparation of Final Compound

Example B.1

a) Intermediate (1) (1.66 g) was added to a solution of 2,6-dichlorobenzene-ethaneimideamide (1.29 g) in DMF (13 mL). The reaction mixture was stirred for 3 days at RT and then for 2 days at 60 ° C. under an argon stream. Water was added and the precipitate was filtered off. This fraction was refluxed in ACN (500 mL), cooled and the precipitate was filtered and dried to give 4-[[4-amino-6-[(2,6-dichlorophenyl) methyl] -1,3,5- 1.58 g (67%, white solid) of triazin-2-yl] amino] benzonitrile (compound 1) were obtained.

b) Compound (1) (0.00135 mol) and acetic anhydride (20 mL) were combined and heated to reflux for 10 minutes. The reaction mixture was then removed from the oil bath and cooled to RT. The precipitate was filtered off to give N- [4-[(4-cyanophenyl) amino] -6-[(2,6-dichlorophenyl) methyl] -1,3,5-triazin-2-yl] -acet 0.25 g (45%) of an amide (compound 22) was obtained.

An increase in reflux time resulted in the disubstituted (compound 40) and trisubstituted (compound 41) homologues of compound 22.

Example B.2

Methanol (120 mL) was added to a mixture of intermediate 5 (2.35 g) and K ₂ CO ₃ (9.19 g) in water (40 mL). The resulting reaction mixture was stirred under argon and refluxed for 19 h. Water (120 mL) was added and the precipitate was filtered off and purified by column chromatography on silica gel (eluent: DCM / 2-propane 90/10). Two desired fractions were combined and their solvents evaporated. The first oil group was slurried in ACN, cooled, filtered and dried to give 4-[[4-amino-6-[(5-chloro-lH-indol-4-yl) methyl] -1,3, 0.75 g (45%, white solid) of 5-triazin-2-yl] amino] benzonitrile (Compound 8, mp. 267-268 ° C) was obtained. The second column fraction group is 4-[[4-amino-6-[(5-chloro-lH-indol-4-yl) methyl] -1,3,5-triazin-2-yl] amino] benzamide 0.15 g of (compound 9) was obtained. After 24 hours at RT, the filtered aqueous solution was filtered to give 0.25 g of compound (9). Combine the two fractions of compound 9, dissolve in 500 ml of reflux methanol, filter under heat, concentrate the filtrate to 50 ml, cool, filter and dry to give 4-[[4-amino-6- [ 0.25 g (14%) of (5-chloro-1H-indol-4yl) methyl] -1,3,5-triazin-2-yl] amino] benzamide (Compound 9, mp. 204-205 ° C.) Got it.

Example B.3

A mixture of compound (1) (1.0 g) and sodium hydride (0.11 g) in DMF (20 mL) was stirred for 20 min at RT under an argon stream. Then 2-isocyanato-propane (0.27 mL) was added dropwise over 30 minutes and the reaction mixture was stirred at RT overnight. Solvent was evaporated and water was added. The residue was filtered off, washed with water and diethyl ether and then recrystallized from 1,4-dioxane. The precipitate was filtered off and dried to give N- [4-[(4-cyano-phenyl) amino] -6-[(2,6-dichlorophenyl) methyl] -1,3,5-triazin-2-yl 0.95 g (85.1%) of] -N '-(1-methylethyl) -urea (Compound 6, mp. 267-268 ° C) was obtained.

Example B.4

A mixture of N- [amino (methylamino) methyl] -2,6-dichloro-benzeneacetamide (4.15 g) and intermediate 6 (3.05 g) in DMF (25 mL) was stirred for 20 hours and refluxed. The solvent was evaporated and the residue was dissolved in DMF (25 mL) and heated at 80 ° C. for 16 h and again at 100-108 ° C. for 66 h. The reaction mixture was cooled, quenched with water, extracted with diethyl ether, washed with dilute NaOH, water, brine and dried over K ₂ CO ₃ . The solvent was evaporated and the residue was purified by column chromatography and recrystallized from 2-propanol and finally in methanol to give 4-[[4- (2,6-dichlorophenyl) methyl] -6- (methyl 0.78 g (12.6%) of -amino) -1,3,5-triazin-2-yl] amino] benzonitrile (compound 7, mp. 229-230 ° C) was obtained.

Example B.5

a) combining intermediate (27) (0.00423 mol), 2-amino-acetamide (0.00431 mol), 1,4-dioxane (20 mL) and N, N-diisopropylethylamine (0.00862 mol) and argon Stir at RT for 16 h. The reaction mixture was quenched with H ₂ O and filtered. The residue was washed with H ₂ O, filtered and then recrystallized in ACN (200 mL). The precipitate was filtered off and dried to give [N- [4-[(4-cyano-phenyl) amino] -6-[(2,6-dichlorophenyl) methyl] -1,3,5-triazine-2- 0.75 g (41.4%) of ethyl] aminoacetamide was obtained.

b) 4-[[4-[(2,6-dichlorophenyl) methyl] -6-hydrazino- in a similar manner as described in Example B.5a, but without using N, N-diisopropylethylamine 1,3,5-triazin-2-yl] amino] benzonitrile (Compound 15) was prepared.

Example B.6

a) Intermediate 27 (0.0128 mol), 1,4-dioxane (50 mL), and O- (trimethylsilyl) hydroxyl-amine (0.134 mol) were bound under argon. The reaction mixture was stirred at RT for 20 h. The reaction mixture was concentrated and DCM (50 mL), NaOH (1 N; 50 mL), and HCl (1 N; 100 mL) were added. The solution was stirred for 1 hour. The precipitate was filtered off and recrystallized in methanol. The precipitate was filtered off and dried to give 4-[[4-[(2,6-dichlorophenyl) methyl] -6- (hydroxyamino) -1,3,5-triazin-2-yl] amino] benzonitrile Monohydrochloride. 2.96 g (59.8%) of monohydrate (Compound 21) was obtained.

b) Compound (21) (0.00227 mol) was stirred in ethyl acetate (50 mL). The mixture was washed with NaHCO ₃ (50 mL saturated solution), then brine, dried, filtered and the solvent was evaporated. The residue is crystallized in methanol, filtered and dried to give 4-[[4-[(2,6-dichlorophenyl) methyl] -6- (hydroxyamino) -1,3,5-triazine-2- 0.60 g (70.6%) of]] amino] benzonitrile (compound 33) was obtained.

Example B.7

A mixture of intermediate 30 (0.068 mol) and 4-amino-benzonitrile (0.0420 mol) in 1,4-dioxane (100 mL) was stirred for 16 hours under argon and refluxed. The hot reaction mixture was filtered and the filtrate obtained was concentrated. The residue was dissolved in DCM (30 mL). The precipitate was filtered off and recrystallized in ACN (250 mL). After cooling to RT, the filtrate was concentrated. The residue was partitioned between DCM / NaOH (3 N). The resulting solution was dried over K ₂ CO ₃ , filtered and the solvent was evaporated. The residue was recrystallized in CH ₃ OH. The precipitate was filtered off and dried to give N, N '-[6-[(2,6-dichlorophenyl) methyl] -1,3,5-triazine-2,4-diyl] bis [4-aminobenzonitrile] 1.00 g (5.0%) of (Compound 11) were obtained.

Example B.8

a) DMF (9.0 mL) and Intermediate 31 (0.00295 mol) were added to sodium hydride (0.00354 mol) under argon. The reaction mixture was stirred for 10 minutes and heated at 80 ° C. for 3.5 hours before adding 4-fluorobenzonitrile (0.00301 mol). After cooling to RT, the reaction mixture was quenched with H ₂ O. The precipitate was filtered off, dried and purified by flash column chromatography on silica gel (eluent: DCM). Gather the desired fractions and evaporate the solvent to afford 4- [4-[(2,6-dichlorophenyl) methyl] -6- (dimethylamino) -1,3,5-triazin-2-yl] amino] -benzo Nitrile (Compound 10) was obtained.

b) Intermediate 31 (0.00671 mol), dimethylacetamide (20 mL), 4-fluorobenzonitrile (0.01007 mol), and K ₂ CO ₃ (0.02685 mol) were combined and refluxed under argon for 4 hours. The reaction mixture was stirred, refluxed overnight, quenched with water and extracted with DCM. The separated organic layer was washed with brine, dried, filtered and the solvent was evaporated. The residue was purified by flash column chromatography (eluent: DCM). The desired fractions were combined and the solvent was evaporated. The residue was crystallized in CH ₃ OH, recrystallized in ACN and finally treated as CH ₃ OH. The precipitate was filtered off and dried to give 4,4 '-[[4-[(2,6-dichlorophenyl) methyl] -6- (dimethylamino) -1,3,5-triazin-2-yl] imino ] 0.32 g of bisbenzonitrile (compound 38) was obtained.

Example B.9

A solution of sodium hydride (0.00195 mol) in DMF (7 mL) was added to compound (1) (0.00186 mol) and the resulting solution was stirred for 5 minutes under argon. Chloroacetic acid methyl ester (0.0186 mol) was then added and the reaction mixture was heated to 70 ° C. for 19 hours. The reaction mixture was then quenched with water and the solid obtained was filtered off. The residue was treated with heated ACN and then filtered while still heated. The residue from the cooled filtrate was recrystallized in 1,4-dioxane. The precipitate was filtered off and methyl N- (4-cyanophenyl) -N- [4-amino-6-[(2,6-dichlorophenyl) methyl] -1,3,5-triazin-2-yl] 0.16 g (19.4%) of glycine (compound 39) was obtained.

Example B.10

Sodium hydride (0.00150 mol), ACN (5 mL), Compound (1) (0.00135 mol) in 1,4-dioxane (10 mL), and ACN (20 mL) were combined under argon. The solution was stirred for 1 hour. 1-Chloro-3-isocyanato-propane (0.00137 mol) was added. The reaction mixture was stirred for 1 hour. 1-methyl-pyrrolidinone (10 mL) was added. The reaction mixture was stirred for 16 hours. Then the mixture was concentrated. The concentrate was partitioned between DCM / H ₂ O. The resulting solution was filtered, dried over K ₂ CO ₃ , filtered and concentrated and the residue treated as NH ₃ in 1,4-dioxane (12 mL, 0.5 M) and heated at 55 ° C. under pressure. The resulting solution was concentrated and further purified by flash column chromatography (eluent: DCM / CH ₃ OH 95/5). Pure oil was collected and the solvent was evaporated to give N- [3-[[4-[(4-cyanophenyl) amino] -6-[(2,6-dichlorophenyl) methyl] -1,3,5-tri 0.12 g (18.9%) of azin-2-yl] amino] propyl] urea (Compound 23) was obtained.

Example B.11

NaOH (0.0128 mol), 1,4-dioxane (5 mL), and guanidine (0.0128 mol) were combined and stirred for 5 minutes at RT under argon. Then intermediate 27 (0.00128 mol) was added and the reaction mixture was stirred at RT for 16 h. The reaction mixture was quenched with H ₂ O and stirred. The obtained precipitate was filtered, the residue was stirred under reflux of methanol, cooled and filtered, and then N- [4-[(4-cyanophenyl) amino] -6-[(2,6-dichlorophenyl) methyl]- 0.34 g (64.3%) of 1,3,5-triazin-2-yl] -guanidine (Compound 20) was obtained.

Example B.12

A mixture of intermediate 27 (0.00256 mol) and 3-amino-1,2-propanediol (0.00563 mol) in 1,4-dioxane (10 mL) and 1-methyl-pyrrolidinone (2 mL) Stir at RT for 48 h. The reaction mixture was concentrated, quenched with DCM / H ₂ O and stirred. The precipitate was filtered off to give (±) -4 [[4-[(2,6-dichlorophenyl) methyl] -6-[(2,3-dihydroxypropyl) amino] -1,3,5-triazine 1.12 g (86.9%) of 2-yl] amino] benzonitrile (compound 26) were obtained.

Example B.13

Compound (1) (0.0016 mol) and 1,1-dimethoxy-N, N-dimethylmethanamine (21 mL) were combined and stirred vigorously at room temperature for 8 hours. The reaction mixture was filtered and the collected solid was washed as ether (fraction A). Further compound was obtained by concentration of the filtrate (fraction B). Combine fractions A and B and recrystallize in ethanol to give 4-[[4- (2,6-dichlorophenyl) methyl] -6-[[(dimethylamino) methylene] amino] -1,3,5-tri 0.15 g of azin-2-yl] amino] benzonitrile (compound 62) was obtained.

Example B.14

A solution of compound 13 (0.000519 mol), LiOH.H ₂ O (0.000571 mol), methanol (5.0 mL) and H ₂ O (5.0 mL) was stirred under argon at RT for 16 h. The reaction mixture was concentrated, redissolved in H ₂ O, acidified with 1.0 N HCl (0.52 mL) and stirred for 3 days. The solution was then filtered, excess 1 N HCl (0.52 mL) and CH ₃ OH were added to the filtrate and the solution was stirred for 16 hours. The obtained precipitate was filtered and dried to give N- [4-[(4-cyanophenyl) -amino] -6-[(2,6-dichlorophenyl) methyl] -1,3,5-triazine-2- 0.18 g (72.7%) of Japanese] glycine (Compound 16) was obtained.

Example B.15

A mixture of compound 32 (0.00378 mol) and NH ₃ in dioxane (50 mL) was heated at 85 ° C. for 9 days in a pressurized container. The solvent was evaporated and the residue obtained was partitioned between DCM / H ₂ O. The organic layer was filtered, washed with ethanol and concentrated to ± 25 mL and filtered to give (±) -2-[[4-[(4-cyanophenyl) amino] -6-[(2,6-dichlorophenyl ) Amino] -6-[(2,6-dichlorophenyl) methyl] -1,3,5-triazin-2-yl] amino-4-hydroxybutanamide (Compound 34) 0.54 g (30.3%) Got it.

Example B.16

The solution of intermediate 27 in dimethylsulfoxide was treated one portion with NaN ₃ and stirred at RT for 28 h. The reaction mixture was poured into ice and then filtered. The precipitate was washed with cold water and recrystallized in ACN to give 4-[[4-azido-6-[(2,6-dichlorophenyl) methyl] -1,3,5-triazin-2-yl] amino] 0.46 g of benzonitrile (compound 68) were obtained.

A list of compounds prepared according to any of the above examples is provided in Tables 2-5.

C. Pharmacological Examples

Example C.1

Acute, hypersensitivity and automated test procedures were used for in vitro evaluation of anti-HIV reagents. Previously known to be very susceptible to HIV infection and to allow replication (Koyanagi et al., Int. J. Cancer, 36, 445-451, 1985), HIV-1 transgenic T-4-cell line, MT-4 Served as the target cell line. Inhibition of the HIV-induced cell modification effect was used as an endpoint. In Vitro Reduction of 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide (MTT) in viability of both HIV- and mock-infected cells reduction) to evaluate with a spectrophotometer. 50% cytotoxic concentration (at CC ₅₀ μΜ) was defined as the concentration of the compound with 50% reduced absorbance of the quasi-infected control sample. The percentage of protection achieved by the compound in HIV-infected cells was calculated by the formula:

In percent,

Wherein (OD _T ) _HIV is the optical density measured as the donor concentration of the test compound in HIV-infected cells; (OD _C ) _HIV is the optical density measured for control untreated HIV-infected cells; (OD _C ) _MOCK is the optical density measured for control untreated pseudo-infected cells; All optical density values were measured at 540 nm. The dose that achieved 50% protection according to the above formula was defined as 50% inhibitory concentration (at ₅₀ μM IC). The ratio of CC ₅₀ to IC ₅₀ was defined as the selectivity index (SI). Compounds of formula (I) are known to effectively inhibit HIV-1. Specific IC ₅₀ , CC ₅₀ and SI values are shown in Table 6 below; The numbers between parentheses in column IC ₅₀ (μM) and CC ₅₀ (μM) give the number of experiments used to calculate mean IC ₅₀ and CC ₅₀ values.

D. Composition Examples

The following formulations embody typical pharmaceutical compositions suitable for systemic or topical administration to patients of animals and humans according to the present invention.

The active ingredient (A.I.) used throughout these examples relates to a compound of formula (I) or a pharmaceutically acceptable acid addition salt.

Example D.1 Film-coated Tablets

Preparation of Tablet Core

A.I. A mixture of 100 g, 570 g of lactose and 200 g of starch was mixed well and then wetted with a solution of 5 g sodium dodecyl sulfate and 10 g polyvinylpyrrolidone in about 200 ml of water. The wet powder mixture was sieved, dried and sieved again. Then 100 g of microcrystalline cellulose and 15 g of hydrogenated vegetable oil were added. The whole was mixed well and compressed into tablets to give 10,000 tablets, each containing 10 mg of active ingredient.

coating

A solution of 5 g of ethyl cellulose in 150 mL of dichloromethane was added to a solution of 10 g of methyl cellulose in 75 mL of modified ethanol. 75 ml of dichloromethane and 2.5 ml of 1,2,3-propanetriol were then added. 10 g of polyethylene glycol was melted and dissolved in 75 mL of dichloromethane. The latter solution was added to the former, followed by 2.5 g of magnesium octadecanoate, 5 g of polyvinylpyrrolidone and 30 ml of concentrated color suspension, and the whole was homogenized. The tablet cores were coated as a mixture so obtained in a coating apparatus.

The compounds of general formula (I) of the present invention exhibit antiretroviral properties, particularly against human immunodeficiency virus (HIV), which is the pathogen of human acquired immunodeficiency syndrome (AIDS). Compounds of the invention also exhibit activity against HIV-1 strains with acquired resistance to non-nucleoside reverse transcriptase inhibitors known in the art. They also have little or no binding affinity for human α-1 acid glycoproteins.

Due to their antiretroviral properties, specifically their anti-HIV properties, especially their anti-HIV-1-activity, the compounds of general formula (I), their pharmaceutically acceptable salts and stereochemically isomeric forms are infected with HIV It is useful in the treatment of individuals and for the prevention of these individuals. In general, the compounds of the present invention may be useful for the treatment of infected warm blooded animals as viruses whose survival is mediated or dependent on the enzyme reverse transscriptase. Symptoms that can be prevented or treated as a compound of the present invention, particularly those associated with HIV and other pathogenic retroviruses, are caused by AIDS, AIDS-related complexes (ARCs), advanced comprehensive lymphadenopathy (PGL), and other retroviruses. Chronic CNS diseases such as HIV mediated dementia and multiple sclerosis.

Claims (17)

Compounds of the general formula (I '), pharmaceutically acceptable acid addition salts and stereochemically isomeric forms thereof: In the above formula, R ¹ and R ² are each independently hydrogen; Hydroxy; Amino; C _1-6 alkyl; C _1-6 alkyloxy; C _1-6 alkylcarbonyl; C _1-6 alkyloxycarbonyl; Ar ¹ ; Mono- or di (Ci_ ₆ alkyl) amino; Mono- or di (Ci_ ₆ alkyl) aminocarbonyl; Dihydro-2 ( 3H ) -furanone; Each independently amino, imino, aminocarbonyl, aminocarbonylamino, hydroxy, hydroxyC _1-6 alkyloxy, carboxyl, mono- or di (C _1-6 alkyl) amino, C _1-6 alkyl Selected from substituted C _1-6 alkyl as one or two substituents selected from oxycarbonyl and thienyl; or R ¹ and R ² can together form pyrrolidinyl, piperidinyl, morpholinyl, azido or mono- or di (C _1-6 alkyl) amino C _1-4 alkylidene; R ³ is hydrogen, Ar ¹ , C _1-6 alkylcarbonyl, C _1-6 alkyl, C _1-6 alkyloxycarbonyl, C _1-6 alkyl substituted with C _1-6 alkyloxycarbonyl; R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently hydrogen, hydroxy, halo, C _1-6 alkyl, C _1-6 alkyloxy, cyano, aminocarbonyl, nitro, amino, tri Selected from halomethyl or trihalomethyloxy; L is C _1-10 alkyl; C _3-10 alkenyl; C _3-10 alkynyl; C _3-7 cycloalkyl; or L is independently C _1-10 alkyl substituted with one or two substituents selected from C _3-7 cycloalkyl; Indolyl or each independently halo, C _1-6 alkyl, C _1-6 alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy, C _1-6 alkylcarbonyl Indolyl substituted as one, two, three or four substituents selected from; Phenyl or each independently halo, hydroxy, C _1-6 alkyl, C _1-6 alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy, C _1-6 alkyl Phenyl substituted as one, two, three, four or five substituents selected from carbonyl; Ar ¹ is phenyl or phenyl each independently substituted with one, two or three substituents selected from halo, C _1-6 alkyl, C _1-6 alkyloxy, cyano, nitro or trifluoromethyl; Provided that the following compounds (a to o) are not included: Co.No. Alk R ¹ / R ² R ³ R ⁴ R ⁵ R ⁶ R ⁷ R ⁸ abcdefghijklmno 1- (4- (2-methylpropyl) phenyl) ethyl1- (4- (2-methylpropyl) phenyl) ethyl1- (4- (2-methylpropyl) phenyl) ethyl1- (4- (2- Methylpropyl) phenyl) ethyl1- (4- (2-methylpropyl) phenyl) ethyl4- (2-methylpropyl) phenylmethyl1- (4- (2-methylpropyl) phenyl) ethyl4- (2-methyl Propyl) phenylmethyl3,4-dimethoxyphenylmethyl2,3-dimethoxyphenylmethyl3,4-diethoxyphenylmethyl2- (3,5- (1,1-dimethylethyl) -4-hydroxy-phenyl ) Ethyl2- (3,5- (1,1-dimethylethyl) -4-hydroxy-phenyl) ethylphenylmethylphenylmethyl H / HH / HH / HH / HH / HH / HH / HH / HH / HH / HH / HH / HH / HH / HH / H HHC ₆ H ₅ HHHHHHHHHHHH CH ₃ HHNO ₂ HHHHHHHHHCH ₃ H HHHHHCF ₃ HHHHHHt-BuHH HNO ₂ HCH ₃ NH ₂ HClHHHHHOHHH HHHHHHHHHHHHt-BuHH HHHHHHHHHHHHHHH The compound of claim 1, wherein R ¹ and R ² are each independently selected from hydrogen, C _1-6 alkyl, Ar ¹ or mono- or di (C _1-6 alkyl) aminocarbonyl; Or R ¹ and R ² can together form pyrrolidinyl, piperidinyl or morpholinyl; R ³ is hydrogen, C _1-6 alkyl or Ar ¹ ; Ar ¹ is phenyl or phenyl each independently substituted with 1, 2 or 3 substituents selected from halo, C _1-6 alkyl, C _1-6 alkyloxy, cyano, nitro or trifluoromethyl; L is a radical of the formula Wherein Alk is C _1-6 alkanediyl; R ^a , R ^b , R ^c , R ^d , R ^e , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently hydrogen, halo, C _1-6 alkyl, C _1-6 alkyloxy, Cyano, aminocarbonyl, nitro, amino, trihalomethyl or trihalomethyloxy; or R ^a and R ^b together can form a divalent radical of the formula -C = H = CH-NR ^9- (a-1), -NR ⁹ -CH = CH- (a-2), Wherein R ⁹ is hydrogen or C _1-4 alkyl. 3. C _3-10 alkenyl or C _1-2 alkyl according to claim 1 or 2, wherein L is independently substituted with one or two substituents selected from C _3-7 cycloalkyl; Indolyl or each independently halo, C _1-6 alkyl, C _1-6 alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy, C _1-6 alkylcarbonyl Indolyl substituted as one, two, three or four substituents selected from among them; Phenyl or each independently halo, hydroxy, C _1-6 alkyl, C _1-6 alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy, C _1-6 alkyl And phenyl substituted as one, two, three, four or five substituents selected from carbonyl. The compound of any one of claims 1-3, wherein L is 2,6-dichlorophenylmethyl. The compound of any one of claims 1-4, wherein R ⁶ is halo, cyano or aminocarbonyl. The compound of any one of claims 1-5, wherein NR ¹ R ² is not amino. The compound of claim 1, wherein the compound is 4-[[4-amino-6-[(2,6-dichlorophenyl) methyl] -1,3,5-triazin-2-yl] amino] benzonitrile; 4-[[4- (2,6-dichlorophenyl) methyl] -6- (hydroxyamino) -1,3,5-triazin-2-yl] amino] benzonitrile or a pharmaceutically acceptable acid moiety thereof Compound that is soluble. 8. A compound according to any one of claims 1 to 7 for use as a drug. Use of a compound of formula (I) for the manufacture of a medicament for the treatment of a patient infected with HIV (human immunodeficiency virus): In the above formula, R ¹ and R ² are each independently hydrogen; Hydroxy; Amino; C _1-6 alkyl; C _1-6 alkyloxy; C _1-6 alkylcarbonyl; C _1-6 alkyloxycarbonyl; Ar ¹ ; Mono- or di (Ci_ ₆ alkyl) amino; Mono- or di (Ci_ ₆ alkyl) aminocarbonyl; Dihydro-2 ( 3H ) -furanone; Each independently amino, imino, aminocarbonyl, aminocarbonylamino, hydroxy, hydroxyC _1-6 alkyloxy, carboxyl, mono- or di (C _1-6 alkyl) amino, C _1-6 alkyl Selected from substituted C _1-6 alkyl as one or two substituents selected from oxycarbonyl and thienyl; or R ¹ and R ² can together form pyrrolidinyl, piperidinyl, morpholinyl, azido or mono- or di (C _1-6 alkyl) aminoC _1-4 alkylidene; R ³ is hydrogen, Ar ¹ , C _1-6 alkylcarbonyl, C _1-6 alkyl, C _1-6 alkyloxycarbonyl, C _1-6 alkyl substituted with C _1-6 alkyloxycarbonyl; R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently hydrogen, hydroxy, halo, C _1-6 alkyl, C _1-6 alkyloxy, cyano, aminocarbonyl, nitro, amino, tri Selected from halomethyl or trihalomethyloxy; L is C _1-10 alkyl; C _3-10 alkenyl; C _3-10 alkynyl; C _3-7 cycloalkyl; or L is independently C _1-10 alkyl substituted with one or two substituents selected from C _3-7 cycloalkyl; Indolyl or each independently halo, C _1-6 alkyl, C _1-6 alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy, C _1-6 alkylcarbonyl Indolyl substituted as one, two, three or four substituents selected from; Phenyl or each independently halo, hydroxy, C _1-6 alkyl, C _1-6 alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy, C _1-6 alkyl Phenyl substituted as one, two, three, four or five substituents selected from carbonyl; Ar ¹ is phenyl or phenyl each independently substituted with one, two or three substituents selected from halo, C _1-6 alkyl, C _1-6 alkyloxy, cyano, nitro or trifluoromethyl. A compound of formula (VII) Wherein W ⁵ is a suitable leaving group and L, R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are as defined in claim 1. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically active amount of a compound according to any one of claims 1 to 7. A method for the preparation of a pharmaceutical composition according to claim 10, which comprises intimately mixing a pharmaceutically acceptable carrier with a therapeutically effective amount of the compound of any one of claims 1-7. a) reacting an intermediate of formula (II) with an intermediate of formula (III) in a reaction-inert solvent to form a compound of formula (I-a); (Wherein R ³ to R ⁸ and L are as defined in claim 1) b) reacting the intermediate of formula (IV) with the intermediate of formula (V) in a reaction-inert solvent to form a compound of formula (I-b); (Wherein R ¹ , R ² , R ⁴ to R ⁵ and L are as defined in claim 1) c) deprotecting the intermediate of formula (VI) according to known deprotection techniques to form a compound of formula (I-c); Wherein n is 1 to 4 and each R 'is independently halo, C _1-6 alkyl, C _1-6 alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl, trihalo Methyloxy, selected from C _1-6 alkylcarbonyl) d) reacting the intermediate of formula (VII) with an amino derivative of formula (VIII) in a reaction inert solvent and in the presence of a suitable base, and then when R ² comprises a protected hydroxy component, Thus removing the protecting group to form a compound of formula (Id); (Wherein W ¹ is a suitable leaving group and R ² to R ⁸ are as defined in claim 1) e) reacting the intermediate of formula (IX) with the intermediate of formula (X) in a reaction inert solvent to form a compound of formula (I-e); Wherein W ² is a suitable leaving group and Ar ¹ and L are as defined in claim 1 f) reacting the intermediate of formula (XI) with the intermediate of formula (XII) in a reaction-inert solvent and in the presence of a suitable base to form a compound of formula (I-f-1); (Wherein W ³ is a suitable leaving group, R ⁴ to R ⁷ are the same as defined in claim 1, wherein R ^{1 'and} R ^2' are the same as hydrogen and the R ¹ and R ² defined in claim 1 no) g) reacting the intermediate of formula (XI-b) with the intermediate of formula (XII-b) in a reaction-inert solvent and in the presence of a suitable base to form a compound of formula (I-f-2); (Wherein W ³ is a suitable leaving group, Ar ¹ is the same as defined in claim 1, wherein R ^{1 'and} R ^2' is not the same as hydrogen and the R ¹ and R ² defined in claim 1) Or, if necessary, the compounds of the formula (I ') are converted to each other according to a known conversion reaction; In addition, if necessary, the compound of general formula (I) is converted into an acid addition salt by treating with an acid, or conversely, the acid addition salt form is converted into a free base by alkali treatment; Process for the preparation of a compound according to claim 1, characterized in that the preparation of stereochemically isomeric forms thereof, if necessary. A combination of a compound of formula (I) as defined in claim 9 with another antiretroviral compound. The combination of claim 14 for use as a drug. A product containing (a) a compound of formula (I) as defined in claim 9, and (b) another antiretroviral compound, as a combination formulation for simultaneous, separate or continuous use in anti-HIV treatment. A pharmaceutical composition comprising (a) a compound of formula (I) as defined in claim 9, and (b) another antiretroviral compound as a pharmaceutically acceptable carrier and active ingredient.